Despite the declining prevalence of chronic disability among older individuals, age continues to be associated with risk of hypertension and hypertension-related diseases, including coronary artery disease and stroke. In this K08 application, the PI will aggressively explore the mechanisms underlying age-related hypertensive disease, especially among those at highest risk. The theoretical underpinnings of the proposed research are based upon data generated by the PI within the Chicago Health, Aging, and Social Relations Study (CHASRS). Funded by the NIA and directed by Dr. John Cacioppo, this study seeks to explain the effect of psychosocial factors, including loneliness, on age-related changes in systolic blood pressure (SBP). Recent data from CHASRS indicate that loneliness and hostility are associated with urinary estrogen metabolite concentrations and these concentrations are associated with SBP. Because diet, exercise, and stress hormones can influence estrogen metabolism, it is hypothesized that many risk factors for hypertension are associated with estrogen metabolism and that serum levels of estrogen metabolites are associated with SBP. The specific aims are designed to explore these hypotheses in the CHASRS cohort and validate them in a larger cohort from the Netherlands Twin Registry. Specific Aim 1 is to determine which serum estrogen metabolite or combination of serum estrogen metabolites best predicts systolic blood pressure in middle aged and older men and women. Specific Aim 2 is to determine the degree to which serum estrogen metabolite concentrations are correlated with urinary estrogen metabolite concentrations. Specific Aim 3 is to determine whether single nucleotide polymorphisms (SNP's) of genes which encode specific estrogen metabolizing enzymes predict the serum concentrations of the estrogen metabolites most closely associated with systolic blood pressure. Specific Aim 4 is to determine the extent to which estrogen metabolites explain the associations between established hypertension risk factors and systolic blood pressure in middle aged and older men and women. Completion of these aims, as well as mentorship by Dr. Cacioppo and additional training in psychology, geriatrics, endocrinology, vascular biology, and genetics, will ensure the PI develops into an independent clinician investigator with expertise in the demographic, psychosocial, and genetic determinants of estrogen metabolism and age-related blood pressure changes.